Sustained release intraocular implants and methods for preventing retinal dysfunction

ABSTRACT

Biocompatible intraocular implants include an alpha-2 adrenergic receptor agonist and a polymer associated with the alpha-2 adrenergic receptor agonist to facilitate release of the alpha-2 adrenergic receptor agonist into an eye for an extended period of time. The alpha-2 adrenergic receptor agonist may be associated with a biodegradable polymer matrix, such as a matrix of a two biodegradable polymers. The implants may be placed in an eye to prevent the occurrence of one or more ocular conditions, or to reduce one or more symptoms of an ocular condition, such as an ocular neurosensory disorder and the like.

BACKGROUND

The present invention generally relates to devices and methods to treatan eye of a patient, and more specifically to intraocular implants thatprovide extended release of a therapeutic agent to an eye in which theimplant is placed, and to methods of making and using such implants, forexample, to prevent retinal dysfunction.

Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline, is analpha-2-selective adrenergic receptor agonist that is effective in thetreatment of open-angle glaucoma by decreasing aqueous humor productionand increasing uveoscleral outflow. Brimonidine is available in twochemical forms, brimonidine tartrate and brimonidine free base.Brimonidine tartrate (Alphagan® P) is publicly available by Allergan fortreating glaucoma. Topical ocular brimonidine formulation, 0.15%Alphagan® P (Allergan, Irvine, Calif.), is currently commerciallyavailable for treatment of open-angle glaucoma. The solubility ofbrimonidine tartrate in water is 34 mg/mL, while the solubility ofbrimonidine freebase is negligible in water.

Recent studies have suggested that brimonidine can promote survival ofinjured retinal ganglion nerve cells by activation of thealpha-2-adrenoceptor in the retina and/or optic nerve. For example,brimonidine can protect injured neurons from further damage in severalmodels of ischemia and glaucoma.

Glaucoma-induced ganglion cell degeneration is one of the leading causesof blindness. This indicates that brimonidine can be utilized in a newtherapeutic approach to glaucoma management in which neuroprotection andintraocular pressure reduction are valued outcomes of the therapeuticregimen. For brimonidine to protect the optic nerve, however, it musthave access to the posterior segment of the eye at therapeutic levels.Currently available techniques for administering brimonidine to theposterior chamber of the eye are not sufficient to address this issue.

Biocompatible implants for placement in the eye have been disclosed in anumber of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224;4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072;5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493.

It would be advantageous to provide eye implantable drug deliverysystems, such as intraocular implants, and methods of using suchsystems, that are capable of releasing a therapeutic agent at asustained or controlled rate for extended periods of time and in amountswith few or no negative side effects.

SUMMARY

The present invention provides new drug delivery systems, and methods ofmaking and using such systems, for extended or sustained drug releaseinto an eye, for example, to achieve one or more desired therapeuticeffects. The drug delivery systems are in the form of implants orimplant elements that may be placed in an eye. The present systems andmethods advantageously provide for extended release times of one or moretherapeutic agents. Thus, the patient in whose eye the implant has beenplaced receives a therapeutic amount of an agent for a long or extendedtime period without requiring additional administrations of the agent.For example, the patient has a substantially consistent level oftherapeutically active agent available for consistent treatment of theeye over a relatively long period of time, for example, on the order ofat least about one week, such as between about two and about six monthsafter receiving an implant. Such extended release times facilitateobtaining successful treatment results.

Intraocular implants in accordance with the disclosure herein comprise atherapeutic component and a drug release sustaining component associatedwith the therapeutic component. In accordance with the presentinvention, the therapeutic component comprises, consists essentially of,or consists of, an alpha-2 adrenergic receptor agonist. The alpha-2adrenergic receptor agonist may be an agonist or agent that selectivelyactivates alpha-2 adrenergic receptors, for example by binding to analpha-2 adrenergic receptor, relative to other types of adrenergicreceptors, such as alpha-1 adrenergic receptors. The selectiveactivation can be achieved under different conditions, but preferably,the selective activation is determined under physiological conditions,such as conditions associated with an eye of a human or animal patient.The drug release sustaining component is associated with the therapeuticcomponent to sustain release of an amount of the alpha-2 adrenergicreceptor agonist into an eye in which the implant is placed. The amountof the alpha-2 adrenergic receptor agonist is released into the eye fora period of time greater than about one week after the implant is placedin the eye and is effective in preventing or reducing retinaldysfunction. The present intraocular implants are useful prophylaxesthat can enhance normal retinal neuronal function. Advantageously, thepresent intraocular implants may be effective in mitigating againstimpending retinal neurosensory dysfunction in retinal disorders inpatients that may have a predisposition or associated risk factors.

In one embodiment, the intraocular implants comprise an alpha-2adrenergic receptor agonist and a biodegradable polymer matrix. Thealpha-2 adrenergic receptor agonist is associated with a biodegradablepolymer matrix that degrades at a rate effective to sustain release ofan amount of the agonist from the implant effective to enhance normalretinal neuronal function. The intraocular implant is biodegradable orbioerodible and provides a sustained release of the alpha-2 adrenergicreceptor agonist in an eye for extended periods of time, such as formore than one week, for example for about three months or more and up toabout six months or more. In certain implants, the alpha-2 adrenergicreceptor agonist is released for about 30-35 days or less. In otherimplants, the alpha-2 adrenergic receptor agonist is released for 40days or more.

The biodegradable polymer component of the foregoing implants may be amixture of biodegradable polymers, wherein at least one of thebiodegradable polymers is a polylactic acid polymer having a molecularweight less than 64 kiloDaltons (kD). Additionally or alternatively, theforegoing implants may comprise a first biodegradable polymer of apolylactic acid, and a different second biodegradable polymer of apolylactic acid. Furthermore, the foregoing implants may comprise amixture of different biodegradable polymers, each biodegradable polymerhaving an inherent viscosity in a range of about 0.3 deciliters/gram(dl/g) to about 1.0 dl/g.

The alpha-2 adrenergic receptor agonist of the implants disclosed hereinmay include quinoxaline derivatives, or other agonists that areeffective in treating ocular conditions. One example of a suitablequinoxaline derivative is brimonidine or brimonidine tartrate. Inaddition, the therapeutic component of the present implants may includeone or more additional and different therapeutic agents that may beeffective in treating an ocular condition.

A method of making the present implants involves combining or mixing thealpha-2 adrenergic receptor agonist with a biodegradable polymer orpolymers. The mixture may then be extruded or compressed to form asingle composition. The single composition may then be processed to formindividual implants suitable for placement in an eye of a patient.

The implants may be placed in an ocular region to treat a variety ofocular conditions. In addition, the implants are effective in preventingor reducing a symptom of retinal dysfunction, such as by enhancingnormal retinal neuronal function. Thus, the present implants may be usedas a prophilaxis to promote a healthy retina and reduce symptomsassociated with retinal dysfunction.

Kits in accordance with the present invention may comprise one or moreof the present implants, and instructions for using the implants. Forexample, the instructions may explain how to administer the implants toa patient, and types of conditions that may be treated with theimplants.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent. In addition, any feature orcombination of features may be specifically excluded from any embodimentof the present invention.

Additional aspects and advantages of the present invention are set forthin the following description and claims, particularly when considered inconjunction with the accompanying drawings.

DRAWINGS

FIG. 1 is a graph showing the cumulative release profiles forbiodegradable brimonidine tartrate containing implants as determined in0.9% phosphate buffered saline at 37 degrees Celsius.

FIG. 2 is a graph similar to FIG. 1 showing the cumulative releaseprofiles for biodegradable brimonidine free base containing implantswith different combinations of biodegradable polymers.

FIG. 3 is a graph similar to FIG. 1 showing the cumulative releaseprofiles for biodegradable brimonidine tartrate containing implantshaving different concentrations of brimonidine tartrate.

FIG. 4 is a graph similar to FIG. 3 showing the cumulative releaseprofiles for biodegradable brimonidine tartrate containing implantshaving different concentrations of brimonidine tartrate and polymericblends.

FIG. 5 is a graph similar to FIG. 4 showing the cumulative releaseprofiles for biodegradable brimonidine free base containing implantshaving different concentrations of brimonidine tartrate and polymericblends.

FIG. 6 is a graph showing the cumulative release profiles forbrimonidine tartrate containing implants (wafers) having differentconcentrations of brimonidine tartrate and polymeric combinations.

FIG. 7 is a graph similar to FIG. 6 showing the cumulative releaseprofiles for biodegradable brimonidine free base containing implantshaving a different concentration of brimonidine tartrate and polymericblends.

FIG. 8 is a graph similar to FIG. 4 showing the cumulative releaseprofiles for biodegradable brimonidine free base containing implantshaving a different concentration of brimonidine tartrate and polymericblends.

FIG. 9 is a graph similar to FIG. 5 showing the cumulative releaseprofiles for biodegradable brimonidine free base containing waferimplants.

FIG. 10 is a graph showing standard ERG potentials (percent of control)as a function of various ERG wave forms for brimonidine treated andplacebo treated rabbits.

DESCRIPTION

As described herein, controlled and sustained administration of atherapeutic agent through the use of one or more intraocular implantsmay improve treatment of undesirable ocular conditions. The implantscomprise a pharmaceutically acceptable polymeric composition and areformulated to release one or more pharmaceutically active agents, suchas alpha-2 adrenergic receptor agonists, over an extended period oftime. The implants are effective to provide a therapeutically effectivedosage of the agent or agents directly to a region of the eye to treator prevent one or more undesirable ocular conditions. Thus, with asingle administration, therapeutic agents will be made available at thesite where they are needed and will be maintained for an extended periodof time, rather than subjecting the patient to repeated injections or,in the case of self-administered drops, ineffective treatment with onlylimited bursts of exposure to the active agent or agents.

An intraocular implant in accordance with the disclosure hereincomprises a therapeutic component and a drug release sustainingcomponent associated with the therapeutic component. In accordance withthe present invention, the therapeutic component comprises, consistsessentially of, or consists of, an alpha-2 adrenergic receptor agonist.The drug release sustaining component is associated with the therapeuticcomponent to sustain release of an effective amount of the alpha-2adrenergic receptor agonist into an eye in which the implant is placed.The amount of the alpha-2 adrenergic receptor agonist is released intothe eye for a period of time greater than about one week after theimplant is placed in the eye, and is effective in preventing retinaldysfunction.

Definitions

For the purposes of this description, we use the following terms asdefined in this section, unless the context of the word indicates adifferent meaning.

As used herein, an “intraocular implant” refers to a device or elementthat is structured, sized, or otherwise configured to be placed in aneye. Intraocular implants are generally biocompatible with physiologicalconditions of an eye and do not cause adverse side effects. Intraocularimplants may be placed in an eye without disrupting vision of the eye.

As used herein, a “therapeutic component” refers to a portion of anintraocular implant comprising one or more therapeutic agents orsubstances used to treat a medical condition of the eye. The therapeuticcomponent may be a discrete region of an intraocular implant, or it maybe homogenously distributed throughout the implant. The therapeuticagents of the therapeutic component are typically ophthalmicallyacceptable, and are provided in a form that does not cause adversereactions when the implant is placed in an eye.

As used herein, a “drug release sustaining component” refers to aportion of the intraocular implant that is effective to provide asustained release of the therapeutic agents of the implant. A drugrelease sustaining component may be a biodegradable polymer matrix, orit may be a coating covering a core region of the implant that comprisesa therapeutic component.

As used herein, “associated with” means mixed with, dispersed within,coupled to, covering, or surrounding.

As used herein, an “ocular region” or “ocular site” refers generally toany area of the eyeball, including the anterior and posterior segment ofthe eye, and which generally includes, but is not limited to, anyfunctional (e.g., for vision) or structural tissues found in theeyeball, or tissues or cellular layers that partly or completely linethe interior or exterior of the eyeball. Specific examples of areas ofthe eyeball in an ocular region include the anterior chamber, theposterior chamber, the vitreous cavity, the choroid, the suprachoroidalspace, the conjunctiva, the subconjunctival space, the episcleral space,the intracorneal space, the epicorneal space, the sclera, the parsplana, surgically-induced avascular regions, the macula, and the retina.

As used herein, an “ocular condition” is a disease, ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. Broadly speaking the eye includes the eyeball and the tissues andfluids which constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve (i.e. the optic disc), and blood vessels and nerves whichvascularize or innervate a posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic opthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

The term “biodegradable polymer” refers to a polymer or polymers whichdegrade in vivo, and wherein erosion of the polymer or polymers overtime occurs concurrent with or subsequent to release of the therapeuticagent. Specifically, hydrogels such as methylcellulose which act torelease drug through polymer swelling are specifically excluded from theterm “biodegradable polymer”. The terms “biodegradable” and“bioerodible” are equivalent and are used interchangeably herein. Abiodegradable polymer may be a homopolymer, a copolymer, or a polymercomprising more than two different polymeric units.

The term “treat”, “treating”, or “treatment” as used herein, refers toreduction or resolution or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of agent needed to treat an ocular condition, orreduce or prevent ocular injury or damage without causing significantnegative or adverse side effects to the eye or a region of the eye.

The term “normal retinal neuronal function” as used herein, refers tothe function of retinal neurons that have not been experimentallydamaged or injured. For example, neurons that have been experimentallyexposed to an ischemic insult or other type of injury or potentiallydamaging situation or condition are specifically excluded from thisdefinition.

Intraocular implants have been developed which can release drug loadsover various' time periods. These implants, which when inserted into aneye, such as the vitreous of an eye, provide therapeutic levels of analpha-2 adrenergic receptor agonist for extended periods of time (e.g.,for about 1 week or more). The disclosed implants are effective intreating ocular conditions, such as posterior ocular conditions, andmore specifically in preventing retinal dysfunction by enhancing normalretinal neuronal function.

In one embodiment of the present invention, an intraocular implantcomprises a biodegradable polymer matrix. The biodegradable polymermatrix is one type of a drug release sustaining component. Thebiodegradable polymer matrix is effective in forming a biodegradableintraocular implant. The biodegradable intraocular implant comprises analpha-2 adrenergic receptor agonist associated with the biodegradablepolymer matrix. The matrix degrades at a rate effective to sustainrelease of an amount of the alpha-2 adrenergic receptor agonist for atime greater than about one week from the time in which the implant isplaced in ocular region or ocular site, such as the vitreous of an eye.

The alpha-2 adrenergic receptor agonist of the implant is typically anagent that selectively activates alpha-2 adrenergic receptors relativeto alpha-1 adrenergic receptors. In certain implants, the alpha-2adrenergic receptor agonist is selectively activates a subtype of thealpha-2 adrenergic receptors. For example, the agonist may selectivelyactivate one or more of the alpha-2a, the alpha-2b, or the alpha-2creceptors, under certain conditions, such as physiological conditions.Under other conditions, the agonist of the implant may not be selectivefor alpha-2 adrenergic receptor subtypes. The agonist may activate thereceptors by binding to the receptors, or by any other mechanism.

In certain implants, the alpha-2 adrenergic receptor agonist is aquinoxaline derivative. The quinoxaline derivatives useful in thepresent implants are those quinoxaline derivatives having the formula,

pharmaceutically acceptable acid addition salts thereof, and mixturesthereof. R₁ and R₂ each is independently selected from the groupconsisting of H, alkyl radicals containing 1 to 4 carbon atoms andalkoxy radicals containing 1 to 4 carbon atoms. R₂ is preferably amethyl radical. The 2-imidazolin-2-ylamino group may be in any of the5-, 6-, 7- and 8-positions, preferably in the 6-position, of thequinoxaline nucleus. R₃, R₄ and R₅ each is located in one of theremaining 5-, 6-, 7- or 8-positions of the quinoxaline nucleus and isindependently selected from the group consisting of Cl, Br, H and alkylradicals containing 1 to 3 carbon atoms. R₃ is preferably in the5-position of the quinoxaline nucleus, and R₄ and R₅ are preferably bothH. In a particularly useful embodiment R₃ is Br.

In at least one implant, R₁ is H and R₂ is selected from alkyl radicalscontaining 1 to 4 carbon atoms. R₃ may advantageously be in the5-position of the quinoxaline nucleus and be selected from H and alkylradicals containing 1 to 3 carbon atoms. All stereoisomers, tautomersand mixtures thereof which comply with the constraints of one or more ofthe presently useful compounds are included within the scope of thepresent invention.

Pharmaceutically acceptable acid addition salts of the compounds of theinvention are those formed from acids which form non-toxic additionsalts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate,phosphate or acid phosphate, acetate, maleate, fumarate, oxalate,lactate, tartrate, citrate, gluconate, saccharate and p-toluenesulphonate salts.

In more specific implants, the quinoxaline derivative has the formula

In additional implants, the alpha-2 adrenergic receptor agonist isprovided as a salt having the formula

The foregoing salt is known as brimonidine tartrate (AGN 190342-F,5-bromo-6-(2-imidazolidinylideneamino)quinoxaline tartrate), and ispublicly available from Allergan, Inc. under the tradename Alphagan®-P.Brimonidine, an organic base, is publicly available as eitherbrimonidine tartrate salt or as brimonidine freebase. The tartrate saltis more soluble than the freebase in various aqueous media. Since boththe tartrate salt and the freebase are chemically stable and havemelting points higher than 200° C., both forms are suitable in formingthe present implants.

Thus, the implant may comprise a therapeutic component which comprises,consists essentially of, or consists of a brimonidine salt, such asbrimonidine tartrate, a brimonidine free base, or mixtures thereof.

The alpha-2 adrenergic receptor agonist may be in a particulate orpowder form and entrapped by the biodegradable polymer matrix. Usually,alpha-2 adrenergic receptor agonist particles will have an effectiveaverage size less than about 3000 nanometers. In certain implants, theparticles may have an effective average particle size about an order ofmagnitude smaller than 3000 nanometers. For example, the particles mayhave an effective average particle size of less than about 500nanometers. In additional implants, the particles may have an effectiveaverage particle size of less than about 400 nanometers, and in stillfurther embodiments, a size less than about 200 nanometers.

The alpha-2 adrenergic receptor agonist of the implant is preferablyfrom about 10% to 90% by weight of the implant. More preferably, thealpha-2 adrenergic receptor agonist is from about 20% to about 80% byweight of the implant. In a preferred embodiment, the alpha-2 adrenergicreceptor agonist comprises about 20% by weight of the implant (e.g.,15%-25%). In another embodiment, the alpha-2 adrenergic receptor agonistcomprises about 50% by weight of the implant.

Suitable polymeric materials or compositions for use in the implantinclude those materials which are compatible, that is biocompatible,with the eye so as to cause no substantial interference with thefunctioning or physiology of the eye. Such materials preferably are atleast partially and more preferably substantially completelybiodegradable or bioerodible.

Examples of useful polymeric materials include, without limitation, suchmaterials derived from and/or including organic esters and organicethers, which when degraded result in physiologically acceptabledegradation products, including the monomers. Also, polymeric materialsderived from and/or including, anhydrides, amides, orthoesters and thelike, by themselves or in combination with other monomers, may also finduse. The polymeric materials may be addition or condensation polymers,advantageously condensation polymers. The polymeric materials may becross-linked or non-cross-linked, for example not more than lightlycross-linked, such as less than about 5%, or less than about 1% of thepolymeric material being cross-linked. For the most part, besides carbonand hydrogen, the polymers will include at least one of oxygen andnitrogen, advantageously oxygen. The oxygen may be present as oxy, e.g.hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylicacid ester, and the like. The nitrogen may be present as amide, cyanoand amino. The polymers set forth in Heller, Biodegradable Polymers inControlled Drug Delivery, In: CRC Critical Reviews in Therapeutic DrugCarrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90,which describes encapsulation for controlled drug delivery, may find usein the present implants.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyvinylalcohol, polyesters, polyethers and combinations thereof which arebiocompatible and may be biodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present invention may include biocompatibility,compatibility with the therapeutic component, ease of use of the polymerin making the drug delivery systems of the present invention, ahalf-life in the physiological environment of at least about 6 hours,preferably greater than about one day, not significantly increasing theviscosity of the vitreous, and water insolubility.

The biodegradable polymeric materials which are included to form thematrix are desirably subject to enzymatic or hydrolytic instability.Water soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Equally important to controlling the biodegradation of the polymer andhence the extended release profile of the implant is the relativeaverage molecular weight of the polymeric composition employed in theimplant. Different molecular weights of the same or different polymericcompositions may be included in the implant to modulate the releaseprofile. In certain implants, the relative average molecular weight ofthe polymer will range from about 9 to about 64 kD, usually from about10 to about 54 kD, and more usually from about 12 to about 45 kD.

In some implants, copolymers of glycolic acid and lactic acid are used,where the rate of biodegradation is controlled by the ratio of glycolicacid to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic acid and lactic acid. Homopolymers, orcopolymers having ratios other than equal, are more resistant todegradation. The ratio of glycolic acid to lactic acid will also affectthe brittleness of the implant, where a more flexible implant isdesirable for larger geometries. The % of polylactic acid in thepolylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some implants,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the intraocular implant may comprisea mixture of two or more biodegradable polymers. For example, theimplant may comprise a mixture of a first biodegradable polymer and adifferent second biodegradable polymer. One or more of the biodegradablepolymers may have terminal acid groups.

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or combination of both. As discussed herein, thematrix of the intraocular implant may release drug at a rate effectiveto sustain release of an amount of the alpha-2 adrenergic receptoragonist for more than one week after implantation into an eye. Incertain implants, therapeutic amounts of the alpha-2 adrenergic receptoragonist are released for no more than about 30-35 days afterimplantation. For example, an implant may comprise brimonidine tartrate,and the matrix of the implant degrades at a rate effective to sustainrelease of a therapeutically effective amount of brimonidine tartratefor about one month after being placed in an eye. As another example,the implant may comprise brimonidine tartrate, and the matrix releasesdrug at a rate effective to sustain release of a therapeuticallyeffective amount of brimonidine for more than forty days, such as forabout six months.

One example of the biodegradable intraocular implant comprises analpha-2 adrenergic receptor agonist associated with a biodegradablepolymer matrix, which comprises a mixture of different biodegradablepolymers. At least one of the biodegradable polymers is a polylactidehaving a molecular weight of about 63.3 kD. A second biodegradablepolymer is a polylactide having a molecular weight of about 14 kD. Sucha mixture is effective in sustaining release of a therapeuticallyeffective amount of the alpha-2 adrenergic receptor agonist for a timeperiod greater than about one month from the time the implant is placedin an eye.

Another example of a biodegradable intraocular implant comprises analpha-2 adrenergic receptor agonist associated with a biodegradablepolymer matrix, which comprises a mixture of different biodegradablepolymers, each biodegradable polymer having an inherent viscosity fromabout 0.16 dl/g to about 1.0 dl/g. For example, one of the biodegradablepolymers may have an inherent viscosity of about 0.3 dl/g. A secondbiodegradable polymer may have an inherent viscosity of about 1.0 dl/g.The inherent viscosities identified above may be determined in 0.1%chloroform at 25° C.

One particular implant comprises brimonidine tartrate associated with acombination of two different polylactide polymers. The brimonidinetartrate is present in about 20% by weight of the implant. Onepolylactide polymer has a molecular weight of about 14 kD and aninherent viscosity of about 0.3 dl/g, and the other polylactide polymerhas a molecular weight of about 63.3 kD and an inherent viscosity ofabout 1.0 dl/g. The two polylactide polymers are present in the implantin a 1:1 ratio. Such an implant provides for release of the brimonidinefor more than two months in vitro, as described herein. The implant isprovided in the form of a rod or a filament produced by an extrusionprocess.

The release of the alpha-2 adrenergic receptor agonist from theintraocular implant comprising a biodegradable polymer matrix mayinclude an initial burst of release followed by a gradual increase inthe amount of the alpha-2 adrenergic receptor agonist released, or therelease may include an initial delay in release of the alpha-2adrenergic receptor agonist followed by an increase in release. When theimplant is substantially completely degraded, the percent of the alpha-2adrenergic receptor agonist that has been released is about one hundred.Compared to existing implants, the implants disclosed herein do notcompletely release, or release about 100% of the alpha-2 adrenergicreceptor agonist, until after about one week of being placed in an eye.

It may be desirable to provide a relatively constant rate of release ofthe alpha-2 adrenergic receptor agonist from the implant over the lifeof the implant. For example, it may be desirable for the alpha-2adrenergic receptor agonist to be released in amounts from about 0.01 μgto about 2 μg per day for the life of the implant. However, the releaserate may change to either increase or decrease depending on theformulation of the biodegradable polymer matrix. In addition, therelease profile of the alpha-2 adrenergic receptor agonist may includeone or more linear portions and/or one or more non-linear portions.Preferably, the release rate is greater than zero once the implant hasbegun to degrade or erode.

The implants may be monolithic, i.e. having the active agent or agentshomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix. Due to ease of manufacture, monolithic implants are usuallypreferred over encapsulated forms. However, the greater control affordedby the encapsulated, reservoir-type implant may be of benefit in somecircumstances, where the therapeutic level of the drug falls within anarrow window. In addition, the therapeutic component, including thealpha-2 adrenergic receptor agonist, may be distributed in anon-homogenous pattern in the matrix. For example, the implant mayinclude a portion that has a greater concentration of the alpha-2adrenergic receptor agonist relative to a second portion of the implant.

The intraocular implants disclosed herein may have a size of betweenabout 5 μm and about 2 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. The vitreous chamber in humans is able to accommodaterelatively large implants of varying geometries, having lengths of, forexample, 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod)with dimensions of about 2 mm×0.75 mm diameter. Or the implant may be acylindrical pellet with a length of about 7 mm to about 10 mm, and adiameter of about 0.75 mm to about 1.5 mm.

The implants may also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant. The total weight of the implant is usuallyabout 250-5000 μg, more preferably about 500-1000 μg. For example, animplant may be about 500 μg, or about 1000 μg. For non-humanindividuals, the dimensions and total weight of the implant(s) may belarger or smaller, depending on the type of individual. For example,humans have a vitreous volume of approximately 3.8 ml, compared withapproximately 30 ml for horses, and approximately 60-100 ml forelephants. An implant sized for use in a human may be scaled up or downaccordingly for other animals, for example, about 8 times larger for animplant for a horse, or about, for example, 26 times larger for animplant for an elephant.

Thus, implants can be prepared where the center may be of one materialand the surface may have one or more layers of the same or a differentcomposition, where the layers may be cross-linked, or of a differentmolecular weight, different density or porosity, or the like. Forexample, where it is desirable to quickly release an initial bolus ofdrug, the center may be a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Alternatively, the center may be polyvinyl alcoholcoated with polylactate, so that upon degradation of the polylactateexterior the center would dissolve and be rapidly washed out of the eye.

The implants may be of any geometry including fibers, sheets, films,microspheres, spheres, circular discs, plaques and the like. The upperlimit for the implant size will be determined by factors such astoleration for the implant, size limitations on insertion, ease ofhandling, etc. Where sheets or films are employed, the sheets or filmswill be in the range of at least about 0.5 mm×0.5 mm, usually about 3-10mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease of handling.Where fibers are employed, the fiber diameter will generally be in therange of about 0.05 to 3 mm and the fiber length will generally be inthe range of about 0.5-10 mm. Spheres may be in the range of 0.5 μm to 4mm in diameter, with comparable volumes for other shaped particles.

The size and form of the implant can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. Larger implants will deliver a proportionately largerdose, but depending on the surface to mass ratio, may have a slowerrelease rate. The particular size and geometry of the implant are chosento suit the site of implantation.

The proportions of alpha-2 adrenergic receptor agonist, polymer, and anyother modifiers may be empirically determined by formulating severalimplants with varying proportions. A USP approved method for dissolutionor release test can be used to measure the rate of release (USP 23; NF18 (1995) pp. 1790-1798). For example, using the infinite sink method, aweighed sample of the implant is added to a measured volume of asolution containing 0.9% NaCl in water, where the solution volume willbe such that the drug concentration is after release is less than 5% ofsaturation. The mixture is maintained at 37° C. and stirred slowly tomaintain the implants in suspension. The appearance of the dissolveddrug as a function of time may be followed by various methods known inthe art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.until the absorbance becomes constant or until greater than 90% of thedrug has been released.

In addition to the alpha-2 adrenergic receptor agonist or alpha-2adrenergic receptor agonists included in the intraocular implantsdisclosed herein, the intraocular implants may also include one or moreadditional ophthalmically acceptable therapeutic agents. For example,the implant may include one or more antihistamines, one or moreantibiotics, one or more beta blockers, one or more steroids, one ormore antineoplastic agents, one or more immunosuppressive agents, one ormore antiviral agents, one or more antioxidant agents, and mixturesthereof.

Pharmacologic or therapeutic agents which may find use in the presentsystems, include, without limitation, those disclosed in U.S. Pat. Nos.4,474,451, columns 4-6 and 4,327,725, columns 7-8.

Examples of antihistamines include, and are not limited to, loradatine,hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine,cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine,diphenylpyraline, phenindamine, azatadine, tripelennamine,dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazinedoxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, andderivatives thereof.

Examples of antibiotics include without limitation, cefazolin,cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan,cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin,cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone,cefadroxil, cephradine, cefuroxime, ampicillin, amoxicillin,cyclacillin, ampicillin, penicillin G, penicillin V potassium,piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin,azlocillin, carbenicillin, methicillin, nafcillin, erythromycin,tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol,ciprofloxacin hydrochloride, clindamycin, metronidazole, gentamicin,lincomycin, tobramycin, vancomycin, polymyxin B sulfate, colistimethate,colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim, andderivatives thereof.

Examples of beta blockers include acebutolol, atenolol, labetalol,metoprolol, propranolol, timolol, and derivatives thereof.

Examples of steroids include corticosteroids, such as cortisone,prednisolone, fluorometholone, dexamethasone, medrysone, loteprednol,fluazacort, hydrocortisone, prednisone, betamethasone, prednisone,methylprednisolone, riamcinolone hexacatonide, paramethasone acetate,diflorasone, fluocinonide, fluocinolone, triamcinolone, derivativesthereof, and mixtures thereof.

Examples of antineoplastic agents include adriamycin, cyclophosphamide,actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin,mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU),methyl-CCNU, cisplatin, etoposide, interferons, camptothecin andderivatives thereof, phenesterine, taxol and derivatives thereof,taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen,etoposide, piposulfan, cyclophosphamide, and flutamide, and derivativesthereof.

Examples of immunosuppresive agents include cyclosporine, azathioprine,tacrolimus, and derivatives thereof.

Examples of antiviral agents include interferon gamma, zidovudine,amantadine hydrochloride, ribavirin, acyclovir, valciclovir,dideoxycytidine, phosphonoformic acid, ganciclovir, and derivativesthereof.

Examples of antioxidant agents include ascorbate, alpha-tocopherol,mannitol, reduced glutathione, various carotenoids, cysteine, uric acid,taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin,cryotpxanthin, astazanthin, lycopene, N-acetyl-cysteine, carnosine,gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid,citrate, Ginkgo Biloba extract, tea catechins, bilberry extract,vitamins E or esters of vitamin E, retinyl palmitate, and derivativesthereof.

Other therapeutic agents include squalamine, carbonic anhydraseinhibitors, alpha agonists, prostamides, prostaglandins, antiparasitics,antifungals, and derivatives thereof.

The amount of active agent or agents employed in the implant,individually or in combination, will vary widely depending on theeffective dosage required and the desired rate of release from theimplant. Usually the agent will be at least about 1, more usually atleast about 10 weight percent of the implant, and usually not more thanabout 80, more usually not more than about 40 weight percent of theimplant.

In addition to the therapeutic component, the intraocular implantsdisclosed herein may include effective amounts of buffering agents,preservatives and the like. Suitable water soluble buffering agentsinclude, without limitation, alkali and alkaline earth carbonates,phosphates, bicarbonates, citrates, borates, acetates, succinates andthe like, such as sodium phosphate, citrate, borate, acetate,bicarbonate, carbonate and the like. These agents advantageously presentin amounts sufficient to maintain a pH of the system of between about 2to about 9 and more preferably about 4 to about 8. As such the bufferingagent may be as much as about 5% by weight of the total implant.Suitable water soluble preservatives include sodium bisulfite, sodiumbisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricborate, phenylmercuric nitrate, parabens, methylparaben, polyvinylalcohol, benzyl alcohol, phenylethanol and the like and mixturesthereof. These agents may be present in amounts of from 0.001 to about5% by weight and preferably 0.01 to about 2% by weight. In at least oneof the present implants, a purite preservative is provided in theimplant, such as when the alpha-2 adrenergic receptor agonist isbrimonidine.

Thus, these implants may contain a therapeutically effective amount ofAlphagan®-P.

In some situations mixtures of implants may be utilized employing thesame or different pharmacological agents. In this way, a cocktail ofrelease profiles, giving a biphasic or triphasic release with a singleadministration is achieved, where the pattern of release may be greatlyvaried.

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the implants. The amount of releasemodulator employed will be dependent on the desired release profile, theactivity of the modulator, and on the release profile of the alpha-2adrenergic receptor agonist in the absence of modulator. Electrolytessuch as sodium chloride and potassium chloride may also be included inthe implant. Where the buffering agent or enhancer is hydrophilic, itmay also act as a release accelerator. Hydrophilic additives act toincrease the release rates through faster dissolution of the materialsurrounding the drug particles, which increases the surface area of thedrug exposed, thereby increasing the rate of drug bioerosion. Similarly,a hydrophobic buffering agent or enhancer dissolve more slowly, slowingthe exposure of drug particles, and thereby slowing the rate of drugbioerosion.

In certain implants, an implant comprising brimonidine or brimonidinetartrate and a biodegradable polymer matrix is able to release ordeliver an amount of brimonidine between about 0.1 mg to about 0.5 mgfor about 3-6 months after implantation into the eye. The implant may beconfigured as a rod or a wafer. A rod-shaped implant may be derived fromfilaments extruded from a 720 μm nozzle and cut into 1 mg size. Awafer-shaped implant may be a circular disc having a diameter of about2.5 mm, a thickness of about 0.127 mm, and a weight of about 1 mg.

The proposed 3-month release formulations may be sterile, andbioerodible in the form of a rod, a wafer or a microsphere containingbrimonidine tartrate within a PLA matrix or POE matrix. The implants aredesigned to delay the clearance of the drug and reduce the need forrepeated implantation over 3-month period, thereby lowering the risk ofcomplications.

Various techniques may be employed to produce the implants describedherein. Useful techniques include, but are not necessarily limited to,solvent evaporation methods, phase separation methods, interfacialmethods, molding methods, injection molding methods, extrusion methods,co-extrusion methods, carver press method, die cutting methods, heatcompression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C.

In addition, the implant may be coextruded so that a coating is formedover a core region during the manufacture of the implant.

Compression methods may be used to make the implants, and typicallyyield implants with faster release rates than extrusion methods.Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

The implants of the present invention may be inserted into the eye, forexample the vitreous chamber of the eye, by a variety of methods,including placement by forceps or by trocar following making a 2-3 mmincision in the sclera. One example of a device that may be used toinsert the implants into an eye is disclosed in U.S. Patent PublicationNo. 2004/0054374. The method of placement may influence the therapeuticcomponent or drug release kinetics. For example, delivering the implantwith a trocar may result in placement of the implant deeper within thevitreous than placement by forceps, which may result in the implantbeing closer to the edge of the vitreous. The location of the implantmay influence the concentration gradients of therapeutic component ordrug surrounding the element, and thus influence the release rates(e.g., an element placed closer to the edge of the vitreous may resultin a slower release rate).

The present implants are configured to release an amount of alpha-2adrenergic receptor agonist effective to prevent or reduce at least onesymptom of an ocular condition, such as retinal dysfunction. Forexample, the implants may be used in a method to prevent retinalneurosensory dysfunction. Thus, the implants may be used in methods ofpreventing or reducing one or more symptoms of an ocular conditionselected from the group consisting of: retinitis pigmentosa, Leber'scongenital amaurosis, retinal degeneration, Usher syndrome, Bardet-Biedlsyndrome, rod-cone dystrophy, choroideremia, gyrate-atrophy, andStargardt's disease. By implanting the alpha-2 adrenergic receptoragonist-containing implants into the vitreous of an eye, it is believedthat the agonist is effective to enhance normal retinal neuronalfunction, thereby preventing retinal dysfunction arising from one ormore disorders or conditions.

In addition, the present implants may be configured to release analpha-2 adrenergic receptor agonist in a therapeutically effectiveamount for a period of time effective to treat glaucoma of a patient.

The implants disclosed herein may also be configured to release thealpha-2 adrenergic receptor agonist or additional therapeutic agents, asdescribed above, which to prevent diseases or conditions, such as thefollowing:

MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARMD),Choroidal Neovascularization, Diabetic Retinopathy, Acute MacularNeuroretinopathy, Central Serous Chorioretinopathy, Cystoid MacularEdema, Diabetic Macular Edema.

UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid PigmentEpitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy,Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), IntermediateUveitis (Pars Planitis), Multifocal Choroiditis, Multiple EvanescentWhite Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis,Serpignous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome,Vogt-Koyanagi-Harada Syndrome.

VASCULAR DISEASES/EXUDATIVE DISEASES: Coat's Disease, ParafovealTelangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle CellRetinopathy and other Hemoglobinopathies, Angioid Streaks, FamilialExudative Vitreoretinopathy.

TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal Disease,Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, HypoperfusionDuring Surgery, Radiation Retinopathy, Bone Marrow TransplantRetinopathy.

PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy andEpiretinal Membranes, Proliferative Diabetic Retinopathy.

INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associated with HIV Infection, Uveitic Disease Associated withHIV Infection, Viral Retinitis, Acute Retinal Necrosis, ProgressiveOuter Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis.

GENETIC DISORDERS: Systemic Disorders with Accosiated RetinalDystrophies, Congenital Stationary Night Blindness, Cone Dystrophies,Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the RetinalPigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy,Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy,pseudoxanthoma elasticum.

RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant RetinalTear.

TUMORS: Retinal Disease Associated with Tumors, Congenital Hypertrophyof the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, ChoroidalOsteoma, Choroidal Metastasis, Combined Hamartoma of the Retina andRetinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumorsof the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior MultifocalPlacoid Pigment Epitheliopathy, Myopic Retinal Degeneration, AcuteRetinal Pigment Epithelitis and the like.

In one embodiment, an implant, such as the implants disclosed herein, isadministered to a posterior segment of an eye of a human or animalpatient, and preferably, a living human or animal. In at least oneembodiment, an implant is administered without accessing the subretinalspace of the eye. For example, a method of treating a patient mayinclude placing the implant directly into the posterior chamber of theeye. In other embodiments, a method of treating a patient may compriseadministering an implant to the patient by at least one of intravitrealinjection, subconjuctival injection, sub-tenon injections, retrobulbarinjection, and suprachoroidal injection.

In at least one embodiment, a method of preventing retinal neuronaldysfunction in a patient comprises administering one or more implantscontaining one or more alpha-2 adrenergic receptor agonists, asdisclosed herein to a patient by at least one of intravitreal injection,subconjuctival injection, sub-tenon injection, retrobulbar injection,and suprachoroidal injection. A syringe apparatus including anappropriately sized needle, for example, a 27 gauge needle or a 30 gaugeneedle, can be effectively used to inject the composition with theposterior segment of an eye of a human or animal. Repeat injections areoften not necessary due to the extended release of the alpha-2adrenergic receptor agonists from the implants.

In another aspect of the invention, kits for treating an ocularcondition of the eye are provided, comprising: a) a container comprisingan extended release implant comprising a therapeutic component includingan alpha-2 adrenergic receptor agonist, such as brimonidine free base orbrimonidine tartrate (e.g., Alphagan-P), and a drug release sustainingcomponent; and b) instructions for use. Instructions may include stepsof how to handle the implants, how to insert the implants into an ocularregion, and what to expect from using the implants.

EXAMPLE 1 Manufacture and Testing of Implants Containing Brimonidine anda Biodegradable Polymer Matrix

Biodegradable implants were made by combining brimonidine tartrate orbrimonidine freebase with a biodegradable polymer composition in astainless steel mortar. The combination was mixed via a Turbula shakerset at 96 RPM for 15 minutes. The powder blend was scraped off the wallof the mortar and then remixed for an additional 15 minutes. The mixedpowder blend was heated to a semi-molten state at specified temperaturefor a total of 30 minutes, forming a polymer/drug melt.

Rods were manufactured by pelletizing the polymer/drug melt using a 9gauge polytetrafluoroethylene (PTFE) tubing, loading the pellet into thebarrel and extruding the material at the specified core extrusiontemperature into filaments. The filaments were then cut into about 1 mgsize implants or drug delivery systems. The rods had dimensions of about2 mm long×0.72 mm diameter. The rod implants weighed between about 900μg and 1100 μg.

Wafers were formed by flattening the polymer melt with a Carver press ata specified temperature and cutting the flattened material into wafers,each weighing about 1 mg. The wafers had a diameter of about 2.5 mm anda thickness of about 0.13 mm. The wafer implants weighed between about900 μg and 1100 μg.

The in-vitro release testing was performed on each lot of implant (rodor wafer) in six replicates initially, and later in four replicates.Each implant was placed into a 24 mL screw cap vial with 10 mL ofPhosphate Buffered Saline solution at 37° C. and 1 mL aliquots wereremoved and replaced with equal volume of fresh medium on day 1, 4, 7,14, 28, and every two weeks thereafter.

The drug assays were performed by HPLC, which consists of a Waters 2690Separation Module (or 2696), and a Waters 2996 Photodiode ArrayDetector. An Ultrasphere, C-18 (2), 5 μm; 4.6×150 mm column heated at30° C. was used for separation and the detector was set at 264 nm. Themobile phase was (10:90) MeOH-buffered mobile phase with a flow rate of1 mL/min and a total run time of 12 min per sample. The buffered mobilephase comprised of (68:0.75:0.25:31) 13 mM 1-Heptane Sulfonic Acid,sodium salt-glacial acetic acid-triethylamine-Methanol. The releaserates were determined by calculating the amount of drug being releasedin a given volume of medium over time in μg/day.

The polymers chosen for the implants are were obtained from BoehringerIngelheim. The polymers were: RG502, RG752, R202H, R203 and R206, andPurac PDLG (50/50). RG502 is (50:50) poly(D,L-lactide-co-glycolide),RG752 is (75:25) poly(D,L-lactide-co-glycolide), R202H is 100% poly(D,L-lactide) with acid end group or terminal acid groups, R203 and R206are both 100% poly(D, L-lactide). Purac PDLG (50/50) is (50:50)poly(D,L-lactide-co-glycolide). The inherent viscosity of RG502, RG752,R202H, R203, R206, and Purac PDLG are 0.2, 0.2, 0.2, 0.3, 1.0, and 0.2dL/g, respectively. The average molecular weight of RG502, RG752, R202H,R203, R206, and Purac PDLG are, 11700, 11200, 6500, 14000, 63300, and9700 daltons, respectively.

A total of 53 formulations were prepared, 31 rods and 22 wafers. Of therod formulations, 4 had release periods longer than 3 months and 3 hadrelease periods longer than 6 months. Of the wafer formulations, 7 hadrelease periods longer than 3 months and 4 had release periods longerthan 4 months.

A list of the rod formulations is shown in Table 1, and a list of waferformulations is shown in Table 2.

TABLE 1 Brimonidine Rod Formulations Formulation Lot BT (w/w) BFB (w/w)Polymer I.V. (dL/g) Core Extr T 1  295-123 50% RG752 0.2 104° C. 2 295-124 50% RG752 0.2 105° C. 3  295-126 50% RG502 0.2 108° C. 4 295-127 50% RG502 0.2 112° C. 5  295-167 50% R203 0.3 98° C. 6  295-16850% R203 0.3 101° C. 7  295-169 50% R206 1.0 118° C. 8  295-170 50% R2061.0 104° C. 9  295-171 25% R206 1.0 98° C. 10  295-172 25% R203 0.3 96°C. 11 453-3  10% 40% R203 0.3 98° C. 12 453-4   5% 20% R203 0.3 96° C.13 453-6  10% 40% R206 1.0 105° C. 14 453-7   5% 20% R206 1.0 104° C. 15453-8   5% 45% R206 1.0 102° C. 16 453-9  15% R206 1.0 102° C. 17 453-1020% (1:1) R203/R206 N/A 98° C. 18 453-11 20% (3:1) R203/R206 N/A 96° C.19 453-12 10% 40% RG752 0.2 108° C. 20 453-13  5% 20% RG752 0.2 104° C.24 453-50 20% R206 1.0 100° C. 25 453-51 17% (1:1) R203/R206 N/A 98° C.26 453-52 40% (1:1) RG752/RG502 N/A 105° C. 27 453-53 40% (3:1)RG752/RG502 N/A 103° C. 28 453-54 40% (1:1) R203/RG502 N/A 103° C. 29453-55 50% R202H 0.2 96° C. 30 453-56 50% R202H 0.2 98° C. 31 453-73 20%RG752 0.2 98° C. 32 453-74 20% Purac (Mw 9700) N/A 95° C. 33 453-75 20%Purac (Mw 9700) N/A 92° C. 53 453-95 20% (2:1) R203/R206 N/A 97° C. BT =Brimonidine Tartrate BFB = Brimonidine Free Base I.V. = InherentViscosity

TABLE 2 Brimonidine wafer Formulations Formu- BT BFB I.V. lation Lot(w/w) (w/w) Polymer (dL/g) 21 453-47 25% R206 1.0 22 453-48 20% (1:1)R203/R206 N/A 23 453-49 20% (3:1) R203/R206 N/A 34 453-76 20% (1:1)R203/R206 N/A 35 453-77 25% R206 1.0 36 453-78 20% (3:1) R203/R206 N/A37 453-79 25% R203 0.3 38 453-80 50% R203 0.3 39 453-81 50% R206 1.0 40453-82 15% R206 1.0 41 453-83 40% (1:1) RG752/RG502 N/A 42 453-84 40%(2:1) RG752/RG502 N/A 43 453-85 40% (1:1) R203/RG502 N/A 44 453-86 50%R202H 0.2 45 453-87 50% (1:1) RG752/RG502 N/A 46 453-88 10% (1:1)R203/R206 N/A 47 453-89 15% (1:1) R203/R206 N/A 48 453-90 10% (3:1)R203/R206 N/A 49 453-91 15% (3:1) R203/R206 N/A 50 453-92 10% R206 1.051 453-93 10% (2:1) R203/R206 N/A 52 453-94 15% (2:1) R203/R206 N/A BT =Brimonidine Tartrate BFB = Brimonidine Free Base I.V. = InherentViscosity

Rod Formulations

The first 10 formulations were prepared with the five differentpolymers, RG752, RG502, R203, R206, and R202H each at 50% w/w drug loadfor both brimonidine tartrate and brimonidine free base. The releaseprofiles are shown in FIG. 1 for brimonidine tartrate and FIG. 2 forbrimonidine free base.

In most cases, formulations prepared with brimonidine tartrate had afaster initial burst than those prepared from brimonidine freebase usingthe same polymer, except for RG502. The data also show that brimonidinefreebase had a lag time of approximately 30 days when formulated inpoly(D, L-lactide) matrix (R203, R206, and R202H), while brimonidinetartrate was released completely on the first day (F5 and F7). This maybe due to the quick dissolution of brimonidine tartrate on the surfaceof the implant.

Several formulations using R203 and R206 with drug doses lower than 50%were prepared, and the release profiles are shown in FIG. 3. Dramaticeffects were observed when the drug load was lowered from 50% down to25%. For example, formulation #9 was prepared with 25% brimonidinetartrate in R206 and it gave a total release of 89% after 105 daysbefore leveling off. Comparing this to formulation #7, which was 50%brimonidine tartrate in R206, and it released 100% in one day.Similarly, formulation #10 was prepared with 25% brimonidine tartrate inR203 and it gave a total release of 90% after 105 days before it leveledoff. Comparing this to formulation #5, which released 74% on day one.

With 20% brimonidine tartrate in R206 (F24), a 14 day lag time ispresent before it started releasing and eventually reaching 89.5%release after 134 days. At 15% brimonidine tartrate in R206 (F16), thelag time increased to 28 days before it started releasing and eventuallyreaching 97.6% after 175 days.

The release profiles of formulation #9 and #10 behaved in an oppositebut complementary way, in that one polymer exhibits early release whilethe other exhibits a delayed release, but both reached the same endpoint at the same time. When both polymers were combined with a lowerdrug load, a more linear and longer release profile would be obtained,as shown in FIG. 4.

The data show that formulation #17, 20% brimonidine tartrate/(1:1)R203/R206, has a desirable in-vitro release profile for a six monthrelease implant. It released approximately 90% of the brimonidinetartrate after 175 days. It was also shown that by varying theproportion of R203 and R206, even with the same drug load (Formulation#17, #18, and #53), different release profiles would result.

Brimonidine freebase formulations with polymer blends were also preparedto see if a more linear release profile could be obtained. Knowing itslow solubility in aqueous media and its release characteristics in eachpolymer, different combinations of RG502-RG752, and RG502-R203 wereprepared, and the release profiles are shown in FIG. 5.

The duration of release for all three formulations was approximately 2months, but all three exhibited a lag time between 1 to 2 weeks. Twoformulations (F32 and F33) were prepared with Purac polymer, PDLG(50/50)-Mw 9700, one with brimonidine tartrate and the one withbrimonidine freebase. Both formulations had fast release with highstandard of deviation; therefore, the release tests were stopped after 7days.

Wafer Formulations

The first set of wafer formulations was prepared from 3 existing rodformulations. Specifically, formulations #9, #17 and #18, with releasereaching 89.4% after 105 days, 89.2% after 175 days, and 102% after 175days, respectively. The release profiles of the first three waferformulations are shown in FIG. 6.

These three formulations had release periods lasting only two to threeweeks, while their rod counterparts had release periods lasting three tofour months. This may be due to the increased surface area of the wafercompared to that of a rod. In the wafer configuration, drug load alsodetermines the duration of drug release. Therefore, drug load wasreduced from 20-25% down to 15% and 10% and the release profiles areshown in FIGS. 7 and 8.

At 15% drug load, formulation #7 had a cumulative release 51.4% after 35days, while formulation #47, 49, and 52 had cumulative releases of93.2%, 92.8% and 88.5%, respectively, after 99 days. The latter threeformulations may be effective as a 4-month drug delivery system.

At 10% drug load, formulations #46, #48, #50, and #51 had cumulativereleases of 83.8%, 98.0%, 92.7% and 89.2%, respectively, after 133 days.These four formulations may be effective as 5-month drug deliverysystems. Both FIGS. 7 and 8 demonstrate that lowering the drug loadyielded not only a longer duration of release but also more linearrelease profiles for all formulations. The figures also show that usinga polymer blend instead of just a single polymer, such as R206, shouldyield a more linear release profile with lower standard of deviations.

Three wafer formulations were prepared from three previous rodformulations #26, #27, and #28, and the release profiles are shown inFIG. 9. The three wafer formulations released slightly faster than theirrod counterparts at day 28 and they were expected to complete theirrelease between days 31 to 55.

CONCLUSIONS

Of the 15 rod formulations prepared from brimonidine tartrate, threeformulations had release periods longer than 3 months (F9, F10, andF53), two formulations had release periods longer than 4 months (F24 andF25), and three formulations had release periods close to 6 months (F16,F17, and F18). Of the 8 rod formulations prepared from brimonidinefreebase, 3 had release periods longer than 2 months (F26, F27, andF28).

Of the 22 wafer formulations, 11 were prepared from brimonidine tartrateand 11 were prepared from brimonidine freebase. Of the 11 waferformulations prepared from brimonidine tartrate, 3 had release periodsof about 4 months (F47, F49, and F52), and 4 had release periods between4 and 5 months (F46, F48, F50, and F51). Of the 11 wafer formulationsprepared from brimonidine freebase, 4 had release periods between 3 and4 months (F35, F36, F38, and F39), and 5 had release periods between oneto two months (F34, F37, F41, F42, and F43).

In general, the wafer formulations prepared from brimonidine tartrate orbrimonidine freebase have faster release than their rod counterparts.

EXAMPLE 2 In Vivo Testing of Intraocular Implants Containing Brimonidineand a Biodegradable Polymer Matrix

Implants containing brimonidine tartrate, such as formulation #17described in Example 1, and placebo implants without a therapeutic agentwere placed in eyes of Dutch Belt pigmented rabbits (2.0-2.5 kg). Twoweeks after implantation, electroretinograms (ERGs) were measured ineach of the eyes of the rabbits as follows. As understood by persons ofordinary skill in the art understand, the ERG reflects the summation ofelectrical responses generated by neurons and non-neuronal cells in theretina and pigment epithelium in response to light. The major ERGcomponents are the fast negative A-wave, the fast positive B-wave andthe slow, positive C-wave. The leading edge of the a-wave provides adirect measure of photoreceptor activity, while the b-wave provides areflection of the action of glial and other cells.

The rabbits were dark adapted for more than 15 minutes. Both eyes weredilated with 1% Tropicamide and 10% Phenelphrine. Animals wereanesthetized with intravenous Ketamine (15 mg/kg) and acepromazine (1mg/kg). A rabbit was placed on a heated platform and a drop ofproparacaine HCL 0.5% was applied before placement of the golden lenscorneal electrode on the eye. Celluvisc was applied between the contactlens electrodes and the cornea in order to improve the comfort andconductivity. Electroretinogram (ERG) recordings were performed using anESPION system (Diagnosys LLC, Littleton, Mass.) with ColorDome Ganzfeld.

An average of 10 trials of ERG and OP responses were recorded forfollowing parameters:

(i) Step-1: 0.1 Hz flash of 0.001 cd.s/m² for low light intensitystimuli;

(ii) Step-2: 0.1 Hz flash of 0.01 cd.s/m² for median light intensitystimuli; and

(iii) Step-3: 0.1 Hz flash of 1 cd.s/m² for high light intensitystimuli; and

(iv) Step-4: 30 Hz flicker of 1 cd.s/m² for high light intensity(average of 30 trials).

Animals were recovered on a heated plate after ERG recordings. Thegolden lens electrodes were carefully cleaned with water and lenscleaner.

ERG results were prepared in a spreadsheet. The data analysis includedan analysis of the B-wave for ERG responses in step-1 to step-3 and theA wave in step-3, as well as the average of the last three peak-to-peakvalues of 30 Hz flicker induced responses and RMS of OP responses offirst 70 msec. The root mean square (RMS) was calculated with theformula: RMS=SQRT(SUM(SQ(X)/70)).

In the eyes that received brimonidine implants, the ERG amplitude wasapproximately 40% greater than in the untreated eyes, as shown in FIG.10. The increase was noted in the B-wave, the A-wave, and the 30 HzFlicker of the ERG waveform.

EXAMPLE 4 Treatment of Ocular Conditions with Various Active Agents

An implant can be formulated with various active agents, including theagents described herein, following the procedures in the Examples above.These implants can provide an extended therapeutic treatment of anocular condition, that is a therapeutic effect during a period of timeduring release of the active agent or after release of all of the activeagent from the implant and during which there is no longer a therapeuticamount of the active agent present at the ocular site at which theimplant was placed. Thus, an implant can be prepared containing analpha-2 adrenergic receptor agonist, such as clonidine, apraclonidine,or brimonidine (available from Allergan, Irvine, Calif. as brimonidinetartrate ophthalmic solution, under the tradename Alphagan®-P). Thus,for example, a brimonidine extended therapeutic treatment implant can beimplanted into an ocular site (i.e. into the vitreous) of a patient withan ocular condition for a desired extended therapeutic effect. Theimplant may contain from about 50 μg to about 500 μg of Alphagan orAlphagan-P depending on the size of the implant. The brimonidineextended therapeutic treatment implant can be implanted into an ocularregion or site (i.e. into the vitreous) of a patient with an ocularcondition for a desired therapeutic effect. The ocular condition can bean inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using the procedure such as trocar implantation. Theimplant can release a therapeutic amount of the active agent to provideand retain a therapeutic effect for an extended period of time tothereby treat a symptom of an ocular condition. For example, the implantmay be effective to improve visual acuity, visual contract sensitivity,or both.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1-20. (canceled)
 21. A method of making a biodegradable intraocularimplant, comprising the step of: extruding a mixture of an alpha-2adrenergic receptor agonist and a biodegradable polymer component toform a biodegradable material that releases drug at a rate effective tosustain release of an amount of the alpha-2 adrenergic receptor agonistfrom the implant effective to enhance normal retinal neuronal functionin an eye in which the implant is placed.
 22. The method of claim 21,wherein the alpha-2 adrenergic agonist is selected from the groupconsisting of quinoxalines, (2-imidozolin-2-ylamino) quinoxalines,5-bromo-6-(2-imidozolin-2-ylamino) quinoxalines, derivatives thereof andmixtures thereof.
 23. The method of claim 21, wherein the alpha-2adrenergic agonist is selected from the group consisting of brimonidine,salts thereof, and mixtures thereof.
 24. The method of claim 21, furthercomprising a step of mixing the alpha-2 adrenergic receptor agonist withthe polymer component before the extrusion step.
 25. The method of claim21, wherein the alpha-2 adrenergic receptor agonist and the polymercomponent are in a powder form.
 26. The method of claim 21, wherein thepolymer component comprises a mixture of biodegradable polymers, atleast one of the biodegradable polymers is a polylactide having amolecular weight of about 64 kD.
 27. The method of claim 21, wherein thepolymer component comprises a mixture of two different biodegradablepolymers, one biodegradable polymer having an inherent viscosity ofabout 0.3 dl/g and the other biodegradable polymer having an inherentviscosity of about 1.0 dl/g. 28-38. (canceled)